The present invention relates to preservative properties of pentetate, particularly the preservative properties of pentetate in an oil-in-water emulsion pharmaceutical composition containing 2,6-diisopropylphenol, i.e. propofol.
Propofol is an injectable anesthetic which can be used to induce and maintain general anesthesia and for sedation, for example, in intensive care units where the duration of treatment may be lengthy. There are a number of known propofol formulations. See, for example, UK 1472793, U.S. Pat. Nos. 4,056,635, 4,452,817, 4,798,846 and 5,714,520.
Propofol formulations have been taught to include preservatives to prevent extrinsic contamination. Ideally, the concentration of preservative is kept to a minimum, especially where the formulation is administered for the maintenance of general anesthesia and sedation where such treatments allow for the possibility of significant amounts of preservative being administered to a patient over the course of treatment. A number of preservatives have been suggested for use in propofol formulations. Oil-in-water formulations present unique requirements which must be satisfied. For instance, for parenteral administration, the preservative must be exerted in the aqueous phase to be effective. However, many ionic species which would exert antimicrobial effects in the aqueous phase tend to destabilize the emulsion. Destabilization of emulsions due to ionic species, and in particular divalent cations, is also known to occur in total parenteral nutrition emulsion systems. Muller et al., Pharm. Ind., Vol 55(10), 948-950 (1993). In addition, to be effective for the intended purpose, namely the prevention of extrinsic contamination, a preservative should be broad spectrum, i.e. effective against gram negative (such as Pseudomonas aeruginosa and Escherichia coli) and gram positive (Staphylococcus aureus) bacteria as well as yeast (such as Candida albicans) at useful concentrations. Edetate has been taught to be the only preservative which was broad spectrum and was exerted in the aqueous phase without destabilizing the oil-in-water propofol formulations. See, U.S. Pat. No. 5,714,520.
Pentetate is known as a metal ion chelator. Holzgraefe, M., et al., Clin. Tox., 24(3), 235-244 (1986). It is also listed by the FDA for use in IV infusions. Inactive Ingredients Guide, FDA, pg. 101 (Doc #139955, Jan 1996). Pentetate has been shown to have inhibitory activity against bacteria in brain-heart infusion broth, J. Dairy Science, Vol. 68, Suppl. 1, 1985, P210. However, Pentetate has not been previously taught as a preservative useful in oil-in-water emulsions.
It has, thus, surprisingly been found that pentetate not only provides suitable preservative properties in oil-in-water emulsions, but does so without destabilizing the emulsion and at significantly lower concentrations than those necessary for edetate to be an effective preservative.